Mark R. Gilbert, Kenneth D. Aldape, Terri S. Armstrong, Jeffrey S. Wefel, Anita Mahajan, and Paul D. Brown, University of Texas MD Anderson Cancer Center; Terri S. Armstrong, University of Texas Health Science Center-School of Nursing, Houston, TX; Meihua Wang and Minhee Won, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Roger Stupp and Monika E. Hegi, Lausanne University Hospitals, Lausanne, Switzerland; Kurt A. Jaeckle, Mayo Clinic Florida, Jacksonville, FL; Deborah T. Blumenthal, Tel Aviv Medical Center, Tel Aviv; Tzahala Tzuk-Shina, Rambam Medical Center, Haifa, Israel; Christopher J. Schultz, Medical College of Wisconsin, Milwaukee, WI; Sara Erridge, University of Edinburgh, Edinburgh, Scotland; Brigitta G. Baumert, Maastricht University Medical Center, Maastricht, the Netherlands; Kristen I. Hopkins, University Hospitals Bristol, Bristol, United Kingdom; Arnab Chakravarti, Arthur G. James Cancer Hospital/Ohio State University Comprehensive Cancer Center, Columbus, OH; Walter J. Curran Jr, Emory University Winship Cancer Center, Atlanta, GA; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
J Clin Oncol. 2013 Nov 10;31(32):4085-91. doi: 10.1200/JCO.2013.49.6968. Epub 2013 Oct 7.
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
替莫唑胺同步和辅助放化疗是新诊断胶质母细胞瘤（GBM）的标准治疗方法。O（6）-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）甲基化状态可能是治疗反应的重要决定因素。剂量密集型（DD）替莫唑胺可导致血液单核细胞和肿瘤中 MGMT 的持续耗竭。本试验旨在研究新诊断的 GBM 患者中，DD 替莫唑胺是否能提高总生存期（OS）或无进展生存期（PFS）。
这项 III 期试验纳入了年龄大于 18 岁、卡氏功能状态评分（KPS）≥ 60 分且有足够组织的患者。分层因素包括临床因素和肿瘤 MGMT 甲基化状态。患者被随机分配至标准替莫唑胺组（第 1 组）或 DD 替莫唑胺组（第 2 组），接受 6-12 个周期的治疗。主要终点为 OS。次要分析评估了 MGMT 状态的影响。
共有 833 名患者被随机分配至第 1 组或第 2 组（1173 名登记）。两组间中位 OS（分别为 16.6 个月和 14.9 个月；风险比 [HR]，1.03；P =.63）或中位 PFS（5.5 个月和 6.7 个月；HR，0.87；P =.06）均无统计学差异。疗效与甲基化状态无关。MGMT 甲基化与 OS（21.2 个月 vs 14 个月；HR，1.74；P <.001）、PFS（8.7 个月 vs 5.7 个月；HR，1.63；P <.001）和反应（P =.012）的改善相关。第 2 组 34%的患者出现≥3 级毒性，高于第 1 组的 53%（P <.001），主要是淋巴细胞减少和疲劳。
本研究未证明新诊断的 GBM 患者使用 DD 替莫唑胺治疗可提高疗效，无论甲基化状态如何。然而，它确实证实了 MGMT 甲基化的预后意义。本研究证明了大规模入组、前瞻性肿瘤采集和分子分层的可行性。
